Recombinant Human Neuregulin-1 in Myocardial Ischaemia-Reperfusion Injury and Chronic Heart Failure

Neuregulin-1, a ligand of the ErbB family of receptor tyrosine kinases is produced by endocardial and myocardial microvascular endothelial cells and acts in a paracrine fashion on adjacent cardiac myocytes. Neuregulin-1-ErbB signalling critically regulates cardiac development and the adaptation of the heart to injury; inhibiting apoptosis, inducing cardiomyocyte proliferation and improving cardiac function and survival in animal models of cardiomyopathy.Neuregulin-1-ErbB signalling also involves pathways involved in protecting against ischaemia-reperfusion injury. This thesis reports the first human studies exploring the acute and chronic haemodynamic responses to a series of recombinant human Neuregulin-1 (rhNeuregulin-1) infusions in patients with stable chronic heart failure and also reports a series of studies aimed at enhancing cardiac preservation in heart transplantation by rhNeuregulin-1 supplementation of a cardiac storage solution. During a 6-hour rhNeuregulin-1 infusion cardiac output increased by 30% (p<0.01), pulmonary artery wedge pressure and systemic vascular resistance decreased 30% and 20% respectively at two hours (p<0.01). A 47% reduction in serum noradrenaline, a 55% reduction in serum aldosterone and a 3.6-fold increase in N-terminal fragment of B-type natriuretic peptide levels were concurrently observed (p<0.001). These acute haemodynamic effects were sustained, as demonstrated by a 12% increase in left ventricular ejection fraction from 32.2±2.0% (baseline) to 36.1±2.3% (mean±1SE, p<0.001) at 84 days. The therapy was well tolerated. In a rodent model of global ischaemia-reperfusion injury, rhNeuregulin-1 supplemented Celsior storage solution improved functional recovery of hearts after 6 hours of hypothermic storage, an effect abrogated by the phosphatidylinositol-3-kinase inhibitor, wortmannin. When storage times were extended out to 10 hours, rhNeuregulin-1 further enhanced cardiac preservation when used in combination with other activators of pro-survival pathways (p<0.01). Functional improvements were accompanied by increased phosphorylation of Akt, extracellular signal-regulated protein kinases 1/2, signal transducer and activator of transcription 3 and glycogen synthase kinase 3β (Western blotting) and a reduction in the cleaved form of caspase-3 (immunohistochemical staining). rhNeuregulin-1produces favourable acute and chronic haemodynamic effects in patients with stable chronic heart failure on optimal medical therapy and improves preservation of the rat heart after prolonged hypothermic storage. It shows promise as a novel therapy in heart failure and transplantation

Clinical deterioration after sildenafil cessation in patients with pulmonary hypertension

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5). Its chronic administration has been shown to improve exercise capacity, World Health Organization functional class, and haemodynamics in patients with symptomatic pulmonary arterial hypertension (PAH). There is however, no data describing the clinical consequences of sudden cessation of sildenafil treatment. In this series, 9 patients with NYHA Class II–IV PAH who were stable on 2 months of sildenafil monotherapy, had their sildenafil ceased to accommodate a 2-week washout period, required for enrollment in research involving an endothelin receptor antagonist. Six minute walk distance (SMWD) and clinical assessments were performed before cessation of sildenafil, and again 2 weeks later. Over the course of this 2-week washout period, 6 of the 9 patients reported increased breathlessness and fatigue, 1 of these was hospitalized with worsening right heart failure. The SMWD fell in 6 patients, with falls of greater than 100 m recorded in 4 patients. This was accompanied by a worsening of NYHA Class from 2.5 ± 0.2 to 3.1 ± 0.1 (mean ± SEM, p = 0.01). These data indicate that sudden cessation of sildenafil monotherapy, in patients with PAH, carries with it a significant and unpredictable risk of rapid clinical deterioration. We recommend that if sildenafil needs to be ceased, it would be more prudent to consider concurrent vasodilator therapy before the gradual cessation of sildenafil

The impact of pediatric emergency department crowding on patient and health care system outcomes: a multicentre cohort study.

BACKGROUND: Emergency department overcrowding has been associated with increased odds of hospital admission and mortality after discharge from the emergency department in predominantly adult cohorts. The objective of this study was to evaluate the association between crowding and the odds of several adverse outcomes among children seen at a pediatric emergency department. METHODS: We conducted a retrospective cohort study involving all children visiting 8 Canadian pediatric emergency departments across 4 provinces between 2010 and 2014. We analyzed the association between mean departmental length of stay for each index visit and hospital admission within 7 days or death within 14 days of emergency department discharge, as well as hospital admission at index visit and return visits within 7 days, using mixed-effects logistic regression modelling. RESULTS: A total of 1 931 465 index visits occurred across study sites over the 5-year period, with little variation in index visit hospital admission or median length of stay. Hospital admission within 7 days of discharge and 14-day mortality were low across provinces (0.8%-1.5% and \u3c 10 per 100 000 visits, respectively), and their association with mean departmental length of stay varied by triage categories and across sites but was not significant. There were increased odds of hospital admission at the index visit with increasing departmental crowding among visits triaged to Canadian Triage and Acuity Scale (CTAS) score 1-2 (odds ratios [ORs] ranged from 1.01 to 1.08) and return visits among patients with a CTAS score of 4-5 discharged at the index visit at some sites (ORs ranged from 1.00 to 1.06). INTERPRETATION: Emergency department crowding was not significantly associated with hospital admission within 7 days of the emergency department visit or mortality in children. However, it was associated with increased hospital admission at the index visit for the sickest children, and with return visits to the emergency department for those less sick